Type 1 diabetes (T1D) arises in genetically predisposed individuals as a consequence of the immune- mediated destruction of pancreatic islet insulin- secreting beta cells. The onset of clinical symptoms of diabetes represents a relative endpoint in the chronic progressive decline of beta cell function, and occurs when a preponderance of beta cell mass is lost. The Diabetes Prevention Trial -Type 1 (DPT-1) and Type 1 Diabetes TrialNet Network have demonstrated that: 1) multi-center cooperative research in T1D can be efficiently coordinated on a national and international level and 2) T1D can be predicted with a high degree of accuracy in relatives of persons with T1D by the presence of autoantibodies and other predisposing metabolic and genetic factors prior to significant hyperglycemia. These studies have enabled identification of a large number of individuals at very early stages of disease. The TrialNet network is committed to further define the pathophysiology of the development of T1D and to conduct clinical trials of interventional agents that may lead to the prevention and/or amelioration of the disease. Indiana University (IU) has been a key member of the TrialNet consortium since its inception in 2003, first as an U.S. Regional Recruitment Center for the DPT-1 study and then as a critical Clinical Center for TrialNet with a wide affiliate network, centrally positioned at the crossroads of Midwestern and Eastern regions. In response to RFA DK-14-016 we outline our accomplishments to date in TrialNet, with a particular focus on leadership in TrialNet trials and studies, our support of collaborative research, our recruitment and outreach plans (including use of affiliate sites in Indiana, Illinois, Michigan, Kentucky, and Ohio), our follow-up and retention plans, and suggestions for increasing the network's cost efficiency. We demonstrate our excellent rates of screening of relatives of persons with T1D through the Pathway to Prevention Study; our solid enrollment and excellent retention for monitoring, prevention, new-onset, and long-term follow-up studies; and our affiliate network expansion by 9 regional sites. In addition, we are engaged in a program of biomarker discovery for prediction and monitoring of progression of T1D and are using the Indiana Clinical and Translational Sciences Institute core resources to identify new patient populations and to explore research barriers to participant participation in open study protocols.